Programmable double-unlock nanocomplex self-supplies phenylalanine ammonia-lyase for precise phenylalanine deprivation of tumors

Essential amino acids (EAAs) deprivation is a potential antitumor approach because EAAs are critical for tumor growth. To efficiently inhibit tumor growth, continuous deprivation of EAAs is required, however, continuous deprivation without precise control will introduce toxicity to normal cells. Herein, a programmable double-unlock nanocomplex (ROCK) was prepared, which could self-supply phenylalanine ammonia-lyase (PAL) to tumor cells for phenylalanine (Phe) deprivation. ROCK was double-locked in physiological conditions when administered systemically. While ROCK actively targeted to tumor cells by integrin αvβ3/5 and CD44, ROCK was firstly unlocked by cleavage of protease on tumor cell membrane, exposing CendR and R8 to enhance endocytosis. Then, hyaluronic acid was digested by hyaluronidase overexpressed in endo/lysosome of tumor cells, in which ROCK was secondly unlocked, resulting in promoting endo/lysosome escape and PAL plasmid (pPAL) release. Released pPAL could sustainably express PAL in host tumor cells until the self-supplied PAL precisely and successfully deprived Phe, thereby blocking the protein synthesis and killing tumor cells specifically. Overall, our precise Phe deprivation strategy effectively inhibited tumor growth with no observable toxicity to normal cells, providing new insights to efficiently remove intratumoral nutrition for cancer therapy.